Renal fibrosis is the final stage of renal diseases. The causes of renal fibrosis include ureteral obstruction.
Ureteral obstruction is one of the most common problems confronting the urologist. Ureteral obstruction causes impedance to the flow of urine in the ureter. Most commonly, obstruction occurs at the ureteropelvic junction. The broader term “obstructive uropathy” can be used to indicate any obstruction to urinary flow occurring between the renal pelvis and the urethra, which causes a developing hydronephrosis and associated renal impairment. Urethral strictures and benign prostatic hypertrophy are cases in point. The incidence of unilateral ureteric obstruction (UUO) is reported as 1/1,000 in adults. Ureteric calculi are the most common cause, and acute obstruction typically presents with significant renal colic as the major symptom. See, for example, Docherty et al., evidence that inhibition of tubular cell apoptosis protects against renal damage and development of fibrosis following ureteric obstruction, Am J Physiol Renal Physiol. 2006 January; 290 (1):F4-13.
In the beginning of UUO, the interstitium is infiltrated by monocytes, which are ‘classically’ activated to macrophages that release cytokines such as TGF-β1 and tumor necrosis factor-α (TNF-α). In turn, TGF-β1 promotes a phenotypic response of tubular epithelial cells either to undergo apoptosis (leading to tubular atrophy) or to undergo epithelial-mesenchymal transition (EMT), becoming fibroblasts that migrate to the interstitium. Angiotensin II (ANG II), produced by the activation of monocytes, stimulates the production of nuclear factor-κB (NF-κB), which leads to the recruitment of more macrophages, as well as to the production of reactive oxygen species (ROS), which aggravates renal tubular injury. In contrast, alternatively activated macrophages can enhance tubular cell survival and proliferation. Endothelial cells can undergo endothelial-mesenchymal transition (EndMT) or apoptosis, which leads to capillary loss and secondary renal ischemia and hypoxia. Resident pericytes and infiltrating hematopoietic stem cells can also differentiate into fibroblasts. Under the stimulus of cytokines, such as TGF-β1 produced by macrophages or other cells, fibroblasts synthesize stress fibers and undergo further differentiation to become myofibroblasts. The myofibroblasts are contractile and augment the deposition of the extracellular matrix (ECM), leading to progressive interstitial fibrosis. This process finally leads to progressive renal fibrosis and irreversible renal failure. See, for example, Chevalier et al., Ureteral obstruction as a model of renal interstitial fibrosis and obstructive nephropathy, Kidney Int. 2009 June; 75 (11):1145-52.
Ginsenosides, the main active ingredients of ginseng, are known to have a variety of pharmacological activities, e.g. antitumor, antidiabetic, antifatique, antiallergic and antioxidant activities. Ginsenosides share a basic structure, composed of gonane steroid nucleus having 17 carbon atoms arranged in four rings. Ginsenosides are metalized in the body, and a number of recent studies suggest that ginsenoside metabolites, rather than naturally occurring ginsenosides, are readily absorbed in the body and act as the active components. Among them, ginsenoside M1 is known as one metabolite of protopanaxadiol-type ginsenosides via the gypenoside pathway by human gut bacteria. Until now, no prior art references report the effect of ginsenoside M1 in treatment of renal fibrosis.